A pervasive problem in many psychiatric disorders, including depression and post-traumatic stress disorder, is the failure to inhibit intense emotional reactions elicited by certain environmental cues. Behavioral interventions often attempt to eliminate these reactions through extinction techniques designed to weaken the ability of environmental cues to trigger problematic responses by severing the relation between the cues and responses. A challenge for the long-term success of this kind of intervention, however, is that the behavior that is suppressed during extinction spontaneously recovers with time, demonstrating that the original memory remains intact after extinction. The experiments outlined in this proposal are designed to examine some circumstances that may lead to the persistence of extinction, thereby weakening any spontaneous recovery effect. Specifically, the aims of the proposal are centered around the role of time in the development and long-term maintenance of extinction of fear in mice. First, we will examine the role of time between extinction experiences to examine the conditions under which different temporal patterns of extinction may suppress fearful memories. Second, we will examine extinction as a function of time since acquisition to see if there are intervals after acquisition in which the fearful memory is particularly vulnerable to the suppressive properties of extinction. Third, we will explore the effects of time since extinction on sensitivity to pharmacological manipulations. Our pharmacological studies will focus on protein kinase A and protein synthesis, two critical molecular processes involved in memory. These pharmacological studies will examine the contribution of the hippocampus to the formation of extinction memories after contextual fear conditioning. At a basic level, determining the course and persistence of extinction after these different treatments will have important implications for current theories of extinction and learning in general. At a clinical level, exploring the behavioral and pharmacological interventions that make the extinction memory long lasting will suggest treatment combinations that may be used to cause lasting suppression of debilitating environmentally triggered responses that underlie many psychiatric disorders. [unreadable] [unreadable] [unreadable]